A hydrogel is a network of cross-linked hydrophilic homo- or hetero-co-polymers, which has the ability to absorb and retain large amounts of water or biological fluids. Hydrogels are of great interest and high demand in industry. Natural and synthetic hydrogels have been utilized as tissue engineering matrices, wound dressings, dermal fillers and drug delivery devices. In particular, injectable hydrogels have received much attention as protein delivery systems that can form a stable depot in the body in situ and release their payloads in a sustained manner. The use of such hydrogels is desirable because it eliminates the need for surgical procedures and allows protein delivery in clinical settings.
However, there are a number of drawbacks that need to be addressed before injectable hydrogels can be efficiently used in clinical settings. For instance, conventional hydrogel systems suffer from a rapid diffusion of proteins from the hydrogel matrix due to their high permeability. Such rapid diffusion, also known as initial burst release, leads to a sudden increase in the concentration of the protein. Hence, if applied to physiological systems, problems such as undesired side effects and ineffective treatment of diseases may arise. Thus, there is a need for hydrogels that have suppressed initial burst release, such that a protein can be released over an extended period of time.
Several approaches have been developed to suppress the initial burst release and extend the release period of the proteins. However, they suffer from a number of drawbacks. At present, the most popular approach is to reduce the permeability of hydrogels by increasing the crosslinking density. However, this approach is not effective in preventing the diffusion of low molecular weight proteins. Thus, there is a need for hydrogels that are effective in preventing the diffusion of low molecular weight proteins.
Another known approach available in the art is the incorporation of heparin in the hydrogel matrices to enable the prolonged release of heparin-binding growth factors due to the specific interaction between heparin and the growth factors. However, a drawback of this approach is that these affinity hydrogel systems are only applicable to a limited range of proteins due to the need for a specific interaction between the proteins and high-affinity ligands. Thus, there is a need for an approach which is suitable for a wider range of proteins.
Another approach that has been used to suppress the initial burst release is pendant chain systems, in which proteins are directly conjugated to polymer chains of hydrogels. The conjugated proteins are released after cleavage of the linker between the proteins and polymer chains via hydrolysis or enzymatic reaction. Since chemical modification of proteins is required, changes to the bioactivity and immunogenicity of the modified proteins may arise. As such, the applicability of this approach is limited. Thus, there is a need for an approach which does not interfere with the bioactivity and immunogenicity of proteins.
There is therefore a need to provide a polymeric system that can suppress the initial burst release that overcomes, or at least ameliorates, one or more of the disadvantages described above.